There is a need for improved organocatalysts and new organocatalytic processes to realize the potential of organocatalysis to streamline the research and development of small molecules as therapeutic leads. The long-term goal is to use organocatalysis in the synthesis of small molecules that treat human illnesses. The objective of this pilot project is to develop improved organocatalysts and new organocatalytic reactions. There are two hypotheses that underlie this research: (1) that acidic double hydrogen bond donors with a rigid achiral scaffold will act as improved organocatalysts, and (2) that new organocatalytic processes can be adapted from reactions catalyzed by bidentate coordination of metals to substrates. The rationale for the proposed research is that once improved organocatalysts and new organocatalytic processes are developed, they can be exploited in the synthesis of small molecules of medicinal value. As this research proposes new methods which can be employed in the synthesis of compounds that can improve human health, it pertains to NIH's mission of fostering the development and application of new strategies for improving health. The hypotheses were generated from published data regarding the efficacy, rational design, and mode of action of related organocatalysts, and will be tested by two specific aims: (1) to identify a new molecular framework for improved organocatalyst systems;and 2) to adapt intramolecular metal-catalyzed reactions as new organocatalytic processes. For both aims, proposed and existing organocatalysts will be synthesized and screened for effectiveness in established and proposed organocatalytic reactions. The proposed research will render organocatalysis more competitive with conventional transition metal catalysis. This is significant because it will advance the utility of organocatalysis, a safer, cheaper and procedurally simpler alternative to transition metal catalysis, in the synthesis of medicinal compounds. The proposed research aims to improve the efficiency and versatility of organic compounds as reaction catalysts or organocatalysts. Despite the fact that organocatalysts are safer, cheaper, and more user-friendly than metal catalysts, the latter are more commonly employed to synthesize compounds of medicinal value because they are more efficient and more versatile. The proposed research will thus help to establish organocatalysts as a superior alternative to metal catalysts for the synthesis of medicinal compounds.